Bis(substituted methyl)-methyl-isoquinoline derivatives and pharmaceutical compositions containing them

ABSTRACT

The invention relates to new bis(substituted methyl)-methyl-isoquinoline derivatives of the formula (I) ##STR1## wherein R 1  and R 2  represent hydroxyl or alkoxy having from 1 to 6 carbon atoms, 
     R 3  is hydrogen, aralkyl having from 1 to 4 carbon atoms in the alkyl moiety or a ##STR2##  group, in which R 4  is alkyl having from 1 to 5 carbon atoms, phenyl, substituted phenyl or --NH--phenyl, 
     X is oxygen or sulfur, 
     R 7  is hydroxyl, halogen or an ##STR3##  group, R 8  is halogen, alkoxy from 1 to 4 carbon atoms or an ##STR4##  group, in which X has the same meaning as defined above, and 
     R 9  independently from R 4  may have the same meanings as defined for R 4 , or is an --NH(C 1-4  -alkyl) or C 3-6  -cycloalkyl group, 
     and salts thereof. According to another aspect of the invention there are provided processes for the preparation of these compounds and pharmaceutical compositions containing them.

The invention relates to new bis(substituted methyl)-methyl-isoquinolinederivatives of the formula (I) ##STR5## wherein R¹ and R² representhydroxyl or alkoxy having from 1 to 6 carbon atoms,

R³ is hydrogen, aralkyl having from 1 to 4 carbon atoms in the alkylmoiety or a ##STR6## group, in which R⁴ is alkyl having from 1 to 5carbon atoms, phenyl, substituted phenyl or --NH-phenyl,

X is oxygen or sulfur,

R⁷ is hydroxyl, halogen or an ##STR7## group, R⁸ is halogen, alkoxyhaving from 1 to 4 carbon atoms or an ##STR8## group, in which X has thesame meaning as defined above, and

R⁹ independently from R⁴ may have the same meanings as defined for R⁴,or is an --NH(C₁₋₄ -alkyl) or C₃₋₆ -cycloalkyl group, and salts thereof.

According to another aspect of the invention there is provided a processfor the preparation of compounds of the formula (I) and salts thereof.

Compounds of the formula (I), in which R⁷ and R⁸ each representshalogen, R¹, R² and R³ are as defined above, may be prepared byhalogenating the corresponding compounds of the formula (II), ##STR9##in which R¹, R² and R³ are as defined above (process a₁). If desired,the compounds obtained may be alkoxylated at place of R⁸ in a mannerknown per se.

Compounds of the formula (I), in which R⁷ and R⁸ each stands for a##STR10## group, wherein X and R⁹ are as hereinbefore defined, R¹, R²and R³ are as defined above, are prepared according to the invention byreacting a compound of the formula (II), in which R¹, R² and R³ are asdefined above, with an acylating agent suitable for incorporating the##STR11## acyl group (process a₂).

According to another process compounds of formula (I) are prepared byconverting an N-substituted bis(hydroxymethyl)-methyl-derivative of theformula (III) ##STR12## into a corresponding O-acyl derivative by N→Oacyl migration (R¹, R², R⁴ and X are as defined above), in the presenceof a catalytic amount of an acid and, if desired, halogenating acompound of the formula (IV) ##STR13## obtained (R¹, R², R⁴ and X are asdefined above) or an acid addition salt thereof and, if desired,splitting off the acyl or thioacyl group from a compound of the formula(V) ##STR14## obtained (R¹, R², R⁴ and X are as defined above, Hal ishalogen) or, if desired, converting a compound of the formula (V)obtained into a corresponding compound of the formula (I), in which R³represents an ##STR15## group (R⁴ and X are as defined above), by O→Nacyl migration, in an alkaline medium.

If desired, the substituents R¹ and/or R² and/or R³ and/or R⁷ and/or R⁸in the compounds of the formula (I) can be converted into other groupswithin the definition of the respective substituents by methods knownper se, or compounds of formula (I) can be converted into their acidaddition salts.

Compounds of the formula (I) are biologically active, thus showimmunsuppressive, antidepressive, analgesic, antipyretic, antihypoxialor gastric acid secretion inhibiting activity. They are further usefulintermediates in the preparation of biologically active2H-azeto[2,1-a]-isoquinoline derivatives, which are disclosed in ourco-pending Hungarian patent application No. 3655/83 which corresponds toU.S. application Ser. No. 664,786 filed Oct. 25, 1984. The lattercompounds may, for example, be prepared by the ring closure of compoundsof the formula (I), in which at least one of R⁷ and R⁸ stands forhalogen, or a salt thereof.

According to Chem. Ber. 102, 915 (1969)1-[bis(hydroxy-methyl)-methyl]-isoquinoline was prepared from1-methyl-isoquinoline with formaldehyde. The compound was afforded in ayield of 60%, after boiling for 40 hours. The only reaction of thecompound obtained examined in this article was its hydrogenation in thepresence of platinum oxide catalyst, which resulted in the corresponding5,6,7,8-tetrahydroisoquinoline in a 30% yield. No N-and/or O-substitutedderivatives of these compounds were prepared, and it was neitherdisclosed nor suggested that the compounds or their derivatives would bepharmaceutically active.

In the above formulae, in the definition of R¹, R² and R⁸ the term"alkoxy" is used to refer to straight or branched chained alkoxy groups,e.g. methoxy, ethoxy, n- or isopropoxy, n-, sec.- or tert.-butoxy, n- orisopentoxy, n- or isohexyloxy groups, depending on the limitation givenfor the number of carbon atoms. The preferred alkoxy groups contain 1 to4 carbon atoms, more preferably they are methoxy or ethoxy.

The term "alkyl" as such or as part of other groups is used to refer tostraight-chained or branched alkyl groups, such as e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,n-pentyl, isopentyl, n-hexyl and isohexyl groups, taking into accountthe limitations for the number of carbon atoms.

The term "aralkyl containing from 1 to 4 carbon atoms in the alkylmoiety" in the definition of R³ preferably represents a C₁₋₄-alkyl-phenyl group, more preferably benzyl.

In the definition of R⁴ and R⁹ "phenyl" may be substituted by one ormore substituents, preferably selected from the group consisting ofhalogen, alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to4 carbon atoms and nitro. The term "halogen" is used to include allhalogen atoms, i.e. fluorine, chlorine, bromine and iodine, preferablychlorine, bromine and iodine, more preferably chlorine.

X preferably stands for oxygen.

Compounds of the formula (I), in which R⁷ is hydroxyl, R⁸ is an##STR16## group (the other substituents are as defined above) areparticularly preferred.

The isoquinoline derivatives of the formula (II), which are used asstarting compounds in processes (a₁) and (a₂) according to theinvention, are new compounds, the preparation of which is disclosed inour co-pending Hungarian patent applications Nos. 3651/83 and 3652/83which correspond respectively to U.S. applications Ser. Nos. 664,842,filed Oct. 25, 1984, and 664,770 filed Oct. 25, 1984. compounds of theformula (II), in which R³ stands for a hydrogen atom, may be prepared byreacting the corresponding 1-methyl-3,4-dihydroisoquinoline derivativesor the corresponding 1-(β-hydroxyethyl)-3,4-dihydroisoquinolinederivatives with formaldehyde or the hydrate or trimeric derivativesthereof, in an alkaline medium, and subsequently hydrogenating theproduct obtained. The compounds in which R³ is other than hydrogen maybe prepared from the N-unsubstituted compounds by reactants suitable forthe introduction of the desired R³ groups, e.g. alkylation,aralkylation, acylation, etc. The 1-methyl- and1-(β-hydroxyethyl)-3,4-dihydroisoquinoline derivatives used for thepreparation of the starting compounds of formula (II) are known in theart and can, for example, be prepared from homoveratryl amine or thecorresponding phenylethyl amine derivatives by acylation andconventional isoquinoline cyclization reactions, e.g.Bischler-Napieralski synthesis.

The N-substituted bis(hydroxymethyl)-methyl isoquinoline derivatives ofthe formula (III) (process b)) are a sub-group of the compounds offormula (II), and can be prepared following the methods used for thepreparation of the latter compounds, starting from the correspondingN-unsubstituted compounds.

Accordng to process (a₁) the compounds of the formula (I), in which R⁷and R⁸ both stand for a halogen, are prepared by halogenatingbis(hydroxymethyl)-methyl isoquinoline derivatives of the formula (II)(R¹, R² and R³ are as hereinbefore defined). The halogenation can beperformed with any conventional halogenating agent, under usualconditions of halogenation. Chlorination may be carried out withchlorine gas, but the reaction is easier to control if for examplesulfinyl dichloride is used as a halogenating agent. Similarly,bromination may be performed with elementary bromine, but it is morepreferred to use e.g. phosphorus tribromide as a brominating agent. Thereaction conditions are selected depending on the concrete reactantsemployed.

According to process (a₂) compounds of the formula (I), in which R⁷ andR⁸ both represent an ##STR17## group, are prepared by reacting acorresponding compound of the formula (II) with a reactant suitable forintroducing an acyl group of the above formula. Depending on the meaningof R⁹, acylation may be performed with an acid halide, acid anhydrideor--if R⁹ is an --NH--C₁₋₄ -alkyl or --NH-phenyl group--with acorresponding isocyanate or isothiocyanate, under reaction conditionsconventional for acylation reactions.

The N-substituted bis(hydroxymethyl)-methyl derivatives of the formula(III) (R¹, R², R⁴ and X are as defined above) can be converted into thecorresponding O-acyl derivatives by N→O acyl migration, with acidcatalysis, N→O acyl migration is a reversible chemical reaction wellknown in the organic chemistry, which proceeds into O→N direction underalkaline conditions [G. Bernath, K. Kovacs, K. L. Lang: Acta Chim. Sci.Hung. 65, 347 (1970)].

If desired, from the compounds, in which R⁷ and/or R⁸ is acyl, the acylgroup(s) can be split off, for example by acid treatment, to yieldcompounds containing hydroxyl group(s) in the respective position(s). Ifdesired, the acyl group(s) can be replaced by other acyl group(s) aswell.

Compounds of the formula (I) can be converted into their acid additionsalts by reaction with suitable acids.

Salt formation can be carried out, for example, in an inert organicsolvent, such as a C₁₋₆ aliphatic alcohol, by dissolving the compound ofthe formula (I) in the solvent and adding the selected acid or asolution thereof formed with the same solvent to the first solutionuntil it becomes slightly acidic (pH 5 to 6). Thereafter the acidaddition salt separates and can be removed from the reaction mixturee.g. by filtration.

The compounds of the formula (I) or the salts thereof, if desired, canbe subjected to further purification, e.g. recrystallization. Thesolvents used for recyrystallization are selected depending on thesolubility and crystallization properties of the compound to becrystallized.

The new compounds of the formula (I) and their physiologicallyacceptable salts may be formulated for therapeutic purposes. Theinvention therefore relates also to pharmaceutical compositionscomprising as active ingredient at least one compound of formula (I) ora physiologically acceptable salt thereof, in association withpharmaceutical carriers and/or excipients. Carriers conventional forthis purpose and suitable for parenteral or enteral administration aswell as other additives may be used. As carriers solid or liquidcompounds, for example water, gelatine, lactose, milk sugar, starch,pectin, magnesium stearate, stearic acid, talc, vegetable oils, such aspeanut oil, olive oil, arabic gum, polyalkylene glycols, and vaseline(registered Trade Mark), can be used. The compounds can be formulated asconventional pharmaceutical formulations, for example in a solid(globular and angular pills, dragees, capsules, e.g. hard gelatinecapsules) or liquid (injectable oily or aqueous solutions orsuspensions) form. The quantity of the solid carrier can be variedwithin wide ranges, but preferably is between 25 mg and 1 g. Thecompositions optionally contain also conventional pharmaceuticaladditives, such as preserving agents, wetting agents, salts foradjusting the osmotic pressure, buffers, flavouring and aromasubstances.

The compositions according to the invention optionally contain thecompounds of formula (I) in association with other known activeingredients. The unit doses are selected depending on the route ofadministration. The pharmaceutical compositions are prepared byconventional techniques including sieving, mixing, granulation, pressingor dissolution of the active ingredients. The formulations obtained arethen subjected to additional conventional treatment, such assterilization.

For the pharmacological tests CFLP (LATI) mice of both sexes, weighing18 to 22 g each and male Han. Wistar (LATI) rats weighing 160 to 180 geach were used. The test materials were administered orally, in 30 mg/kgdoses, in the form of a suspension containing 5% of Tween 80, one hourbefore the tests.

TEST METHODS

1. Maximum electroshock (mice)

The shock was applied through a corneal electrode (20 mA, 0.2 msec, HSESchockgerat typ. 207). The animals which do not show a tonic, extensoricspasm as a result of electroshock treatment are considered protected(See Swinyard et al.: J. Pharmacol. Exp. Ther. 106, 319 (1952)).

2. Metrazole spasm (mice)

After pretreatment, the animals were administered 125 mg/kg ofpentylenetetrazole subcutaneously. The animals which did not show (a) aclonic, (b) a tonic extensoric spasm and which survived the experimentwere regarded protected.

Observation time: one hour (Everett L. M. and Richards R. K.: J.Pharmacol. Exp. Ther. 81, 402 /1944/).

3. Inhibition of tetrabenazine catalepsy

The test was carried out on male rats each weighing 160 to 180 g. Thetest materials were administered intraperitoneally, in a dose of 30mg/kg, one hour before tetrabenazine administration. The animals, whichif their forlegs were placed on a 7 cm high pillar, did not correcttheir bizarre position within 30 seconds were regarded cataleptic (DelayJ. and Denicker P.: Compt. Rend. Congr. Med. Alenistens Neurologists 19,497 /Luxemb./).

4. Analgesic activity (mice)

One hour after pretreatment, mice were administered 0.4 ml of a 0.6%acetic acid solution intraperitoneally, as a pain stimulus. Thefrequency of writhing syndrom is registered for 30 minutes. The changesobserved as a result of treatment with the test compounds are related tothe mean value of the frequency of writhing syndrom in the controlgroup, and the difference is expressed in percentage (Koster R. et al.:Exp. Ther. 72:74 /1941/).

5. Antipyretic activity (rats)

Hyperthermia is induced in rats with Brewer's yeast suspension (0.5% ofBrewer's yeast, 1% of arabic gum in a volume of 0.3 ml, s.c.). Theanimals are treated with the test materials 4 hours later, and thetracheal temperature of the animals is registered with an ELABthermometer (typ. TE-3) for 4 hours. The antipyretic activity isexpressed in percentage of the animals which have an at least onecentrigrade lower temperature than the average of the control grouptreated with the solvent (Nimegeers C. J. E. et al.: ArzneimittelForsch. 25:15/9 /1975/).

The analgesic activity of1-[1'-(hydroxymethyl)-1'-(benzoyl-oxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride (compound A) and1-[1'-(hydroxymethyl)-1'-(m,p,m'-trimethoxybenzoyloximethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride (compound B) is 4-times and 3.7-times, respectively,higher than that of Na-salycilate. The test results are set forth inTable 1.

                                      TABLE 1                                     __________________________________________________________________________            Antispasm activity                                                                       Antitetra-                                                         max.       benazine                                                                            Analgesic                                                                           Antipyretic                                            electro-                                                                           metrazole                                                                           activity                                                                            activity                                                                            activity                                       Substances                                                                            shock                                                                              a  b  (%)   (%)   (%)                                            __________________________________________________________________________    Compound A                                                                            20.0 -- 20.0                                                                             35.0.sup.x                                                                          28.0.sup.x                                                                          10.0                                           Compound B                                                                            --   -- 20.0                                                                             --    30.0.sup.x                                                                          30.0                                           Na--salycilate                                                                        --   -- 20.0                                                                             --    113.0.sup.x                                                                         110.0.sup.x                                    __________________________________________________________________________

The invention is elucidated in detail by the aid of the followingnon-limiting Examples.

EXAMPLE 1 Preparation of1-[bis(chlormethyl)-methyl]-2-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

(A)1-[bis(Hydroxymethyl)-methyl]-2-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

0.01 mole (2.7 g) of1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineis dissolved in 50 ml of benzene with slight warming, and a solution of0.015 mole (0.6 g) of sodium hydroxide in 10 ml of water is added to thesolution. 0.011 mole (0.5 g) of benzoyl chloride is added dropwise tothe reaction mixture, under cooling and stirring. When the addition ofacid chloride is complete, the mixture is stirred at room temperaturefor one hour, whereupon the organic phase is separated, and the aqueousphase is extracted twice with chloroform. The combined organic phasesare dried and evaporated to yield the aimed compound.

Melting point: 161° to 163° C. (methanol/ether). Yield: 95%. Analysisfor C₂₁ H₂₅ NO₅ (371.43): calculated: C 67.91%, H 6.78%, N 3.77%; found:C 67.72%, H 6.98%, N 4.00%.

(B) To 0.01 mole (3.7 g) of1-[bis(hydroxymethyl)-methyl]-2-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineprepared according to Step (A)

0.04 mole (5 ml) of sulfinyl dichloride is added under ice cooling, inabout 5 to 10 minutes. The reaction mixture is allowed to stand at roomtemperature for 24 hours, whereupon the excess of sulfinyl chloride isevaporated, the residue is cooled, alkalized with sodium bicarbonatesolution, and extracted with three 30-ml portions of ether. The extractis dried over sodium sulfate and evaporated to about 10 ml. Upon coolingthe aimed compound is obtained in a crystalline form.

Melting point: 170° to 171° C. (ethanol). Yield: 53%. Analysis for C₂₁H₂₃ Cl₂ NO₃ (408.31): calculated: C 61.77%, H 5.68%, N 3.43%, Cl 17.39%;found: C 61.35%, H 5,95%, N 3.80%, Cl 17.76%.

EXAMPLE 2 Preparation of1-[1'-(hydroxymethyl)-1"-(benzoyloxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

0.01 mole (3.7 g) of1-[bis(hydroxymethyl)-methyl]-2-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineprepared according to Step A of Example 1 is dissolved in 20 ml ofabsolute ethanol. An excess amount of an absolute ethanolic hydrogenchloride solution is added to the solution and the reaction mixture isthen refluxed for 4 hours. Thereafter the reaction mixture isevaporated, and the obtained crystalline product is recrystallized fromabsolute ethanol.

Melting point: 211° to 214° C. Yield: 95%. Analysis for C₂₁ H₂₆ ClNO₅(407.90): calculated: C 61.84%, H 6.42%, N 3.43%; found: C 61.78%, H6.55%, N 3.60%.

The compounds set forth in Table 1 can be prepared in an analogousmanner, by proper selection of the starting substances. The reflux time,depending on the substituent of the acyl group, is between one and sixhours.

                                      TABLE 1                                     __________________________________________________________________________    1-[1'-(Hydroxymethyl)-1'-(O--acyl)-methyl]-6,7-dialkoxyl-1,2,3,4-tetrahydr    oisoquinoline                                                                 hydrochlorides of formula (I/1)                                                                          Melting point                                                        Formula/ Mole-                                                                         (°C.)                                                                         Analysis    Yield                           Example                                                                            R.sup.1 = R.sup.2                                                                  R.sup.9 cular weight                                                                           Solvent  calculated                                                                          found                                                                             (%)                             __________________________________________________________________________    3    CH.sub.3 O                                                                         CH.sub.3                                                                              C.sub.16 H.sub.24 ClNO.sub.5                                                           208-210                                                                              C:                                                                              55.57 55.97                                                                             93                                                345.82   ethanol                                                                              H:                                                                              7.00  7.37                                                                  N:                                                                              4.05  4.20                                4    C.sub.2 H.sub.5 O                                                                  CH.sub.3                                                                              C.sub.18 H.sub.28 ClNO.sub.5                                                           193-197                                                                              C:                                                                              57.82 58.07                                                                             91                                                373.86   ethanol                                                                              H:                                                                              7.55  7.92                                                                  N:                                                                              3.75  3.54                                5    C.sub.2 H.sub.5 O                                                                  C.sub.6 H.sub.5                                                                       C.sub.23 H.sub.30 ClNO.sub.5                                                           182-184                                                                              C:                                                                              63.37 62.96                                                                             87                                                435.95   ethanol/                                                                             H:                                                                              6.94  7.20                                                           ether  N:                                                                              3.21  3.39                                6    CH.sub.3 O                                                                         C.sub.6 H.sub.4 CH.sub.3 ( -p)                                                        C.sub.22 H.sub.28 ClNO.sub.5                                                           221-222                                                                              C:                                                                              62.62 62.37                                                                             82                                                421.95   abs.   H:                                                                              6.69  7.06                                                           ethanol                                                                              N:                                                                              3.32  3.41                                7    C.sub.2 H.sub.5 O                                                                  C.sub.6 H.sub.4 CH.sub.3 ( -p)                                                        C.sub.24 H.sub.32 ClNO.sub.5                                                           187-189                                                                              C:                                                                              64.07 63.32                                                                             85                                                449.95   EtOH   H:                                                                              7.17  7.55                                                           ether  N:                                                                              3.11  2.57                                8    CH.sub.3 O                                                                         C.sub.6 H.sub.4 Cl( -p)                                                               C.sub.21 H.sub.25 Cl.sub.2 NO.sub.5                                                    220-223                                                                              C:                                                                              57.02 56.80                                                                             95                                                442.34   methanol                                                                             H:                                                                              5.70  5.93                                                                  N:                                                                              3.17  3.25                                9    C.sub.2 H.sub.5 O                                                                  C.sub.6 H.sub.4 Cl( -p)                                                               C.sub.23 H.sub.29 Cl.sub.2 NO.sub.5                                                    189-192                                                                              C:                                                                              58.73 58.79                                                                             90                                                470.40   ethanol                                                                              H:                                                                              6.21  5.99                                                                  N:                                                                              2.98  2.95                                10   C.sub.2 H.sub.5 O                                                                  C.sub.6 H.sub.4 NO.sub.2 ( -p)                                                        C.sub.23 H.sub.29 ClN.sub.2 O.sub.7                                                    195-198                                                                              C:                                                                              57.32 57.13                                                                             85                                                481.95   ethanol/                                                                             H:                                                                              6.06  6.38                                                           ether  N:                                                                              5.81  5.52                                11   CH.sub.3 O                                                                         C.sub.6 H.sub.3 (OCH.sub.3).sub.2                                                     C.sub.23 H.sub.30 ClNO.sub.7                                                           148-150                                                                              C:                                                                              59.03 58.48                                                                             78                                        ( --m,  -p)                                                                           467.94   ethanol                                                                              H:                                                                              6.46  6.07                                                                  N:                                                                              2.99  3.21                                12   C.sub.2 H.sub.5 O                                                                  C.sub.6 H.sub.3 (OCH.sub.3).sub.2                                                     C.sub.25 H.sub.34 ClNO.sub.7                                                           127-131                                                                              C:                                                                              60.54 60.12                                                                             78                                        ( --m,  -p)                                                                           495.98   ethanol                                                                              H:                                                                              6.91  7.23                                                                  N:                                                                              2.82  2.85                                13   CH.sub.3 O                                                                         C.sub.6 H.sub.2 (OCH.sub.3).sub.3                                                     C.sub.24 H.sub.32 ClNO.sub.8                                                           160-162                                                                              C:                                                                              57.88 57.70                                                                             75                                        ( --m,  -p,  --m)                                                                     497.97   ethanol                                                                              H:                                                                              6.48  6.96                                                                  N:                                                                              2.81  3.17                                14   C.sub.2 H.sub.5 O                                                                  C.sub.6 H.sub.2 (OCH.sub.3).sub.3                                                     C.sub.26 H.sub.36 ClNO.sub.8                                                           155-162                                                                              C:                                                                              59.37 59.53                                                                             78                                         --m,  - p,  --m)                                                                     526.03   ethanol                                                                              H:                                                                              6.90  7.21                                                                  N:                                                                              2.66  2.86                                15   CH.sub.3 O                                                                         C.sub.6 H.sub.3 Cl.sub.2 ( --m,  -p)                                                  C.sub.21 H.sub.24 Cl.sub.3 NO.sub.5                                                    173-176                                                                              C:                                                                              52.90 52.05                                                                             79                                                476.78   ethanol                                                                              H:                                                                              5.07  5.39                                                                  N:                                                                              2.94  2.90                                16   C.sub.2 H.sub.4 O                                                                  C.sub.6 H.sub.3 Cl.sub.2 ( --m,  -p)                                                  C.sub.23 H.sub.28 Cl.sub.3 NO.sub.5                                                    135-140                                                                              C:                                                                              54.72 54.52                                                                             89                                                504.83   ethanol                                                                              H:                                                                              5.59  5.52                                                                  N:                                                                              2.77  2.57                                __________________________________________________________________________

EXAMPLE 17 Preparation of1-[bis(chloromethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

0.01 mole (3.0 g) of1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride is powdered and suspended in 6.5 ml of sulfinyldichloride. The mixture is then slightly heated under stirring for 30minutes. The excess of sulfinyl dichloride is distilled off under vacuum(ejector jet pump), the residue is taken up in benzene and evaporated todryness. The obtained oily residue is crystallized from a mixture ofethanol and ether.

Melting point: 216° to 219° C. Yield: 76%. Analysis for C₁₄ H₂₀ Cl₃ NO₂(340.68): calculated: C 49.36%, H 5.92%; found: C 49.76%, H 6.12%.

The corresponding diethoxy analogue can be prepared from1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride in an analogous manner.

Melting point: 149° to 153° C. (ethanol/ether). Yield: 73%. Analysis forC₁₆ H₂₄ Cl₃ NO₂ (368.73): calculated: C 52.12%, H 6.56%; found: C52.65%, H 6.37%.

EXAMPLE 18 Preparation of1-[bis(bromomethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinolinehydrobromide

To a suspension of 0.01 mole (3.5 g)1-[bis-(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinolinein 30 ml of absolute benzene 0.03 mole (20 ml) of phosphorus tribromideis portionwise added, under ice cooling and stirring. The reactionmixture is refluxed for 45 minutes. After cooling 20 ml of cold waterare added, and the mixture is refluxed for additional 10 minutes. Aftercooling, the two phases are separated, and the benzene phase isextracted with two 20-ml portions of water. The combined aqueous phasesare washed with two 20-ml portions of diethyl ether. The aqueous phaseis then adjusted to pH 8 with sodium hydroxide and extracted with four30-ml portions of ether. The extract is dried and evaporated. A solutionof hydrogen bromide in absolute ethanol is added to the residue to yield1-[bis(bromomethy)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinolinehydrobromide in a crystalline form.

Melting point: 188° to 190° C. (ethanol/ether). Yield: 78%. Analysis forC₁₆ H₂₄ Br₃ NO₂ (502.09): calculated: C 38.27%, H 4.82%, N 2.79%; found:C 38.26%, H 4.92%, N 2.87%.

EXAMPLE 19 Preparation of1-[bis(bromomethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinolinehydrobromide

To 0.01 mole (2.7 g) of1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline100 ml of absolute tetrachloromethane are added, and the solution issaturated with hydrogen bromide gas under ice cooling. The solvent isevaporated under reduced pressure to yield the hydrobromide of thestarting substance as a viscous mass. To this residue 0.03 mole (20 ml)of phosphorus tribromide is added, and the mixture is heated on a waterbath for 4 hours. After cooling, the aimed compound is separated fromthe reaction mixture as a crystalline substance. The compound isfiltered off and thoroughly washed with absolute ether or absoluteacetone. The physical and spectroscopical data of the compound obtainedare identical with those of the compound prepared according to Example18.

EXAMPLE 20 Preparation of1-[1'-(chloromethyl)-1"-(benzoyloxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

Starting from1-[1'-(hydroxymethyl)-1"-(benzoyloxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineprepared according to Example 2, otherwise following the proceduredescribed in Example 1, Step (B), the aimed compound is obtained with amelting point (after crystallization from 96% ethanol) of 196° to 198°C.

Analysis for C₂₁ H₂₅ Cl₂ NO₂ (426.25): calculated: C 59.14%, H 5.91%, N3.25%, Cl 16.63%; found: C 60.54%, H 6.20%, N 3.44%, Cl 16.58%.

EXAMPLE 21 Preparation of1-[1'-(chloromethyl)-1"-(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

0.01 mole (4.26 g) of1-[1'-(chloromethyl)-1"-(benzoyloxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride prepared according to Example 20 is boiled in a mixture of50 ml of a 10% aqueous hydrogen chloride solution and 10 ml of ethanolfor 2.5 hours. After evaporation the aimed compound is obtained in acrystalline form.

Melting point (after recrystallization from 96% ethanol): 216°-219° C.Yield: 67%. Analysis for C₁₄ H₂₁ Cl₂ NO₃ (322.23): calculated: C 52.18%,H 6.56%, N 4.34%, Cl 22.00%; found: C 52.68%, H 6.56%, N 4.48%, Cl21.86%.

EXAMPLE 22 Preparation of1-[bis(phenylcarbamoyloxymethyl)-methyl]-2-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

(A)1-[bis(Hydroxymethyl)-methyl]-2-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride

0.01 mole (3.7 g) of the N-benzoyl compound prepared according toExample 1, Step A is reacted with 3 g of lithium tetrahydroaluminate(III) in absolute tetrahydrofuran. The reaction mixture is refluxed for3 hours, worked up in a usual manner, and is then coverted into theaimed hydrochloride salt

Melting point: 177° to 179° C. (ethanol/ether). Yield: 69%. Analysis forC₂₁ H₂₈ ClNO₄ (393.90): calculated: C 64.03%, H 7.16%, N 3.56%; found: C63.65%, H 7.53%, N 3.12%.

(B) 0.01 mole of the compound obtained in Step (A) is boiled with 0.02mole of phenyl isocyanate for 4 to 6 hours. Evaporation of the reactionmixture yields the aimed compound in a crystalline form.

Melting point: 185° C. (toluene). Analysis for C₃₅ H₃₇ N₃ O₆ (595.70):calculated: C 70.57%, H 6.26%, N 7.05%; found: C 70.09%, H 6.33%, N6.54%.

The compounds of formula (I/2) set forth in Table 2 can be prepared inan analogous manner, by proper selection of the starting substances.

                                      TABLE 2                                     __________________________________________________________________________    Compounds of formula (I/2)                                                                                       Analysis                                                         Formula                                                                              Melting                                                                             Calculated                                                       Molecular                                                                            point (°C.)                                                                  found                                      Example                                                                            R.sup.1 = R.sup.2                                                                  R.sup.3                                                                              R.sup.9                                                                            weight Solvent                                                                             C  H  N                                    __________________________________________________________________________    23   CH.sub.3 O                                                                         COC.sub.3 H.sub.5                                                                    NHC.sub.4 H.sub.9                                                                  C.sub.31 H.sub.43 N.sub.3 O.sub.7                                                    87 benzene:                                                                         65.36                                                                            7.61                                                                             7.37                                                       569.70       65.30                                                                            7.77                                                                             6.98                                 24   CH.sub.3 O                                                                         COC.sub.6 H.sub.5                                                                    NHC.sub.6 H.sub.5                                                                  C.sub.35 H.sub.35 N.sub.3 O.sub.2                                                    182-184                                                                             68.95                                                                            5.79                                                                             6.89                                                       609.68 benzene                                                                             69.81                                                                            6.17                                                                             6.97                                 25   CH.sub.3 O                                                                         COCH.sub.3                                                                           NHC.sub.6 H.sub.5                                                                  C.sub.30 H.sub.33 N.sub.3 O.sub.7                                                    164-165                                                                             65.80                                                                            6.07                                                                             7.67                                                       547.61 benzene                                                                             65.44                                                                            7.07                                                                             8.28                                 26   CH.sub.3 O                                                                         CONHC.sub.6 H.sub.5                                                                  NHC.sub.6 H.sub.5                                                                  C.sub.35 H.sub.36 N.sub.4 O.sub.7                                                    173-174                                                                             67.29                                                                            5.81                                                                             8.97                                                       624.70 benzene                                                                             69.48                                                                            5.79                                                                             9.25                                 __________________________________________________________________________

EXAMPLE 27 Preparation of1-[bis(phenylcarbamoyloxymethyl)-methyl]-2-(phenylcarbamoyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

0.01 mole of1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineis reacted with 0.03 mole of phenylisocyanate in toluene, as describedin Example 22. The aimed compound is obtained, which has the samephysical and analytical characteristics as the product of Example 26(Table 2).

EXAMPLE 28 Preparation of1-[1'-(hydroxymethyl)-1"-(benzoyloxymethyl)-methyl]-2-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

0.01 mole (4.08 g) of1-[1'-(hydroxymethyl)-1"-(benzoyloxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride is suspended in 50 ml of benzene, and to the suspension 25ml of a 2M aqueous sodium hydroxide solution are added. 0.011 mole ofbenzoyl chloride is added with stirring to the reaction mixture and themixture is stirred at room temperature for one hour. The organic phaseis separated and the aqueous phase is extracted with two 50-ml portionsof benzene. Drying and evaporation of the combined organic phases yieldsthe aimed compound in a crystalline form.

Melting point: 135° to 138° C. (benzene). Yield: 85%. Analysis for C₂₈H₂₉ NO₆ (475.56): calculated: C 70.72%, H 6.15%, N 2.95%; found: C71.05% H 5.92%, N 3.01%.

EXAMPLE 29 Preparation of1-[1'-(hydroxymethyl)-1"-(benzoyloxymethyl)-methyl]-2-(N'-phenyl-thiocarboxamido)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

5 mmoles (2.04 g) of1-[1'-(hydroxymethyl)-1"-(benzoyloxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride are dissolved in 20 ml of water, to the solution 5 ml of a10% aqueous sodium hydroxide solution are added and it is then extractedwith three 20-ml portions of benzene. The combined benzene phases aedried, whereupon 5 mmoles of phenyl isothiocyanate are added. After 24hours the precipitated product is filtered off and crystallized fromethanol to yield the aimed compound.

Melting point: 155° to 158° C. Yield: 79%. Analysis for C₂₈ H₃₀ N₂ O₅ S(506.61): calculated: C 66.38%, H 5.97%, N 5.53%; found: C 66.58%, H6.35%, N 5.16%.

We claim:
 1. Bis(substituted methyl)methylisoquinoline derivatives ofthe formula (I), ##STR18## wherein R¹ and R² represent hydroxyl oralkoxy having from 1 to 6 carbon atoms,R³ is hydrogen, phenyl C₁ -C₄-alkyl; or a ##STR19## group, in whichR⁴ is alkyl having from 1 to 5carbon atoms, unsubstituted phenyl, phenyl substituted by halogen, alkylhaving from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbon atomsor nitro or --NH-phenyl, X is oxygen or sulfur, R⁷ is hydroxyl, halogenor an ##STR20## group, R⁸ is halogen, alkoxy having from 1 to 4 carbonatoms or an ##STR21## group, in which X has the same meaning as definedabove, and R⁹ independently from R⁴ may have the same meanings asdefined for R⁴, or is an --NH(C₁₋₄ -alkyl) or C₃₋₆ -cyclogroup,andphysiologically acceptable salts thereof.
 2. A compound of the formula(I) as defined in claim 1, wherein X is oxygen.
 3. A compound of theformula (I) as defined in claim 1, wherein R⁷ is hydroxyl and R⁸ is an##STR22## group.
 4. The compound of the formula (I) as defined in claim1 which is1-[1'-(hydroxymethyl)-1'-(benzoyloxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroixoquinolinehydrochloride.
 5. The compound of the formula (I) as defined in claim 1which is1-[1'-(hydroxymethyl)-1'-(m,p,m'-trimethoxybenzoyloxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride.
 6. A pharmaceutical composition having immunsuppressive,anti-depressive, analgesic, anti-pyretic, antihypoxial, and gastric acidinhibiting activity comprising as active ingredient an effective amountof at least one compound of formula (I) as defined in claim 1 orphysiologically acceptable salts thereof, in association withpharmaceutical carriers and/or excipients.